Over 34 million Americans have used cocaine and >1.5 million are estimated to use this agent habitually. Cocaine causes severe cardiotoxicity and stimulates reactive oxygen species (ROS) production leading to left ventricle hypertrophy and dysfunction. We showed that cocaine administration to mice transgenic for HIV-1 worsens left ventricle hypertrophy, causes premature death and induces pathological changes that are more severe than those observed in wild-type mice. Cocaine use predisposes to human immunodeficiency virus (HIV-1) infection and HIV/AIDS. In the developed world, HIV-1 infection is commonly treated with anti-retroviral drugs that have untoward cardiovascular effects, including cardiomyopathy. Cardiomyopathy in HIV/AIDS patients is prevalent (6%), and has a poor prognosis. Research from our laboratory and others has shown that gene products of HIV-1 and antiretroviral drugs alter mitochondrial function, stimulate mitochondrial production of ROS, and cause heart failure. The cardiovascular system is particularly prone to interactions and complications from cocaine and HIV/AIDS, however, mechanisms are poorly understood. We propose that the interaction of HIV/AIDS, antiretroviral nucleosides, and cocaine causes alterations in cardiomyocytes through undefined mechanisms that lead to cardiomyopathy and heart failure (Figure 1). The complexity of each scenario requires a systems biology approach to understand their interactions and illuminate therapeutic options. The following aims will be addressed: Aim 1: To define how nDNA genetic and epigenetic events in HIV/AIDS, antiretroviral therapy, and cocaine administration impact cardiomyopathy in vivo. Aim 2: To define genetic and epigenetic events from HIV/AIDS and cocaine that impact mRNA expression and mDNA abundance in the heart. Aim 3: To prevent cardiomyopathy in HIV/AIDS, cocaine, and antiretrovirals by ameliorating oxidative stress. Our team is uniquely qualified to address the aims. We will employ a multidisciplinary approach to study transcriptional and epigenetic analysis, physiological and biochemical phenotyping and novel mathematical systems analyses to unravel this complex problem. PUBLIC HEALTH RELEVANCE: Cardiomyopathy is linked to HIV/AIDS and cocaine, but those clinical interactions are complex: The purpose of this application is to use a systems biological analytical approach to dissect complex interactions between pathological, physiological, biochemical and genetic events in HIV/AIDS and cocaine. Ultimately, information obtained may help to formulate testable hypotheses about pathogenesis and treatment of cardiomyopathy in HIV/AIDS and cocaine.